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Exogenous Ketones: What They Are, Benefits Of Use And How They Work

Exogenous ketones have become an increasingly popular nutritional/ dietary supplement since they were introduced in 2014. Like with any new supplement of interest, though, there tends to be a lot of misinformation that you have to sift your way through to find the reliable data.

Therefore, this article will do the hard work for you and get right into what the true benefits and drawbacks of exogenous ketones are. We will also cover what forms of ketones to consider, how they function in the body, and their role in future research.

 

What Are Ketones?

Ketones are used by our bodies (our mitochondria) to generate energy. They are an alternative fuel source to glucose.

Generic Ketone Structure

Biochemically speaking, ketones are organic (carbon-based) compounds that contain a central carbon atom double-bonded to an oxygen atom and two carbon-containing substituents, denoted by “R” (see chemical structure on the figure).  Ketones are considered simple compounds because of their small molecular structure and weight.

In humans, there are 3 different ketones (referred to as ketone bodies) produced in mitochondria of the liver: acetone, acetoacetic acid, and beta-hydroxybutyric acid (BHB).

 

Beta-Hydroxybutyric Acid 

Also commonly referred to as Beta Hydroxybutyrate or just BHB. Other chemical names include 3-hydroxybutyric acid or 3-hydroxybutyrate.

BHB is not technically a ketone since it contains a reactive OH-group in place of where a double-bonded oxygen normally would be as you can see in the diagram below.

However, BHB still functions like a ketone in the body and can be converted to energy (via acetoacetate and then acetyl-CoA), much like acetoacetate and acetone can (though acetone conversion to acetyl-CoA is not efficient, due to the requirement to convert acetone to acetoacetate via decarboxylation).

 

Structures of Ketone Bodies

Exogenous Ketone Bodies Explained

Exogenous ketone bodies are just ketone bodies that are ingested through a nutritional supplement. Ketone bodies produced in the liver are more properly referred to as endogenous ketone bodies.

Exogenous = Originates from a source external from the body.
Endogenous = Originates from a source internal to the body.

 

Most supplements rely on BHB as the source of their exogenous ketone bodies. BHB is converted to acetoacetic acid and then some quantity converted to acetone through a acetoacetate decarboxylase waste pathway, the acetone will be excreted. Some of the acetoacetic acid will enter the energy pathway using beta-ketothialase, which converts acetoacetic acid to two Acetyl-CoA molecules. The Acetyl-CoA is then able to enter the Krebs cycle and generate ATP. Essentially, exogenous ketone body supplements provide users with an instant supply of ketones to utilize, even if you’re not necessarily in a state of ketosis prior to ingestion (such as when eating a higher-carb diet). Although the research is in its early stages and more data is needed to understand what long-term effects occur when elevated blood ketone levels are combined with a carbohydrate based diet.

A common question is why BHB is the go-to ketone body for exogenous ketone supplements. The likely reason is that BHB is the most efficient and easy to formulate nutritional supplement ketone body. As the body efficiently converts BHB to acetoacetic acid, BHB has the desired effect in raising plasma ketone levels.

Are “Raspberry Ketones” The Same As “Ketone Bodies”?

Raspberry ketone has become an increasingly popular ingredient used in fat-loss and general health supplements. However, despite its name, it has no relation to ketone bodies. This has created some confusion for people interested in exogenous ketone supplements.

Raspberry ketone is in fact a phenolic compound that gives raspberries their pleasant smell. It is structurally similar to the stimulant synephrine. Despite the marketing it doesn’t appear to have much effect on fat loss.1

Takeaway: Ignore information and products related to raspberry ketones, they have nothing to do with exogenous ketones and beta hydroxybutyrate.

Ketone Salts Vs. Ketone Esters

Exogenous ketones of beta hydroxybutyrate (BHB) are available in two forms:

  1. Ketone Salts:Naturally-derived compounds that simply mix sodium (and/or potassium, or calcium) with BHB to improve absorption. Commercially available supplements are all made from ketone salts currently (includes KetoForce, KetoCaNa and Keto OS). These are also sometimes called “Ketone Mineral Salts” of “BHB Mineral Salts”.
  2. Ketone Esters: Synthetically-made compounds that link an alcohol to a ketone body, which is metabolized in the liver to a ketone. Ketone esters are used primarily in research (at the moment) for testing their efficacy in elevating ketone body levels (below is a generic structure of a BHB ester). They also are reportedly very unpleasant tasting, according to those who have experimented with them.

Structure of a BHB Ester

Currently, the commercially available supplements for personal use are all made from the ketone salts. Ketone esters are only used in research at this time.

The ketone esters raise blood levels of beta hydroxybutyrate to higher levels than the ketone salts. There is also strong evidence that ketone esters are more effective than ketone salts as far as their physiological benefits go. It is not clear why this happens, but could be because of a difference in the absorption rate in the GI tract.

However, esters tend to be a little tougher to tolerate (due to gut distress after ingestion) and don’t have the most pleasant taste (as mentioned earlier).

Figure 1 2 below shows a comparison of the effects of various ketone supplements on body weight changes, in rats, over 4 weeks. Ketone esters were the most effective at reducing weight gain over the 4-week period. However, the point must be made that by week 4 BHB salts and BHB salts + MCT oil had matched the total body weight loss of the ketone esters. This may suggest that ketone esters have a greater initial impact, then plateaus as the body weight stabilises to a new equilibrium):

 

Figure 1: Effect of Exogenous Ketone Supplements on Body Weight

The supplements included:

  • BMS (Beta-hydroxybutyrate Mineral Salt) – sodium/ potassium based (similar to KetoForce)
  • MCT (medium chain triglyceride oil)
  • BMS + MCT (1:1 mixture of beta-hydroxybutyrate mineral salt and MCT oil)
  • KE (Ketone Ester – 1,3 butanediol acetoacetate diester)
  • BD (1,3-butanediol)

Benefits Of Exogenous Ketone Use

Exogenous ketone supplements may provide a multitude of benefits, ranging from athletic performance enhancement, more efficient weight loss, cancer prevention, cognitive improvement, anti-inflammatory properties, and more.

Weight Loss Goals

  • Appetite suppression: As shown above in figure 1, a 4-week trial done on rats showed that exogenous ketones were effective at reducing weight gain. It is likely that this reduction in weight gain was the result of the exogenous ketones reducing the overall food intake.
  • The fate of excess ketones: In the event someone has an excessive amount of ketones in the blood, the body (specifically the kidneys) will work as quickly as possible to filter out ketones via urine rather than converting them to adipose tissue. 3 This is not to say that you can’t gain fat if you consume an exorbitant amount of exogenous ketones, but that they are less prone to be converted to fat than other nutrients.
  • More tolerable than MCT oil: MCT oil has been known to cause gastrointestinal distress in users, especially when taken in higher amounts. Exogenous ketones in the form of ketone salts, in comparison, are generally well-tolerated. Thus they enable one to avoid adverse GI events while providing the body with similar types of benefits (see Ref. 2). Figure 1 shows that MCT oil can be effective in reducing body weight. A combination of MCT oil and exogenous ketones may aid weight loss and allow a lower loading of ketone supplements, without the GI distress seen with MCT oil.

Performance Goals

  • Athletic enhancement: Exogenous ketone supplementation has a promising outlook for enhancing athletic performance for a variety of reasons. Firstly, ingested ketone bodies induce an acute ketosis that lasts for several hours and mimics the physiology of starvation.Secondly, exogenous ketones present a way to elevate ketone levels without having depleted muscle glycogen stores (low muscle glycogen is well known to impair sustained physical performance). 4 This being said, at this time there is little direct data that shows performance enhancements after ingesting exogenous ketones. A very well formulated study by Volek et al. 5 has shown that fat adapted athletes have much higher glycogen stores than was previously anticipated and the athletes can replenish glycogen stores as efficiently as athletes on a carbohydrate based diet.  The hypothetical premise behind their use is sound nevertheless.
  • Improved cognition: Elevated plasma ketone concentrations divert the brain to utilize ketone bodies for synthesis of phospholipids, which drives growth and myelination. Normally, glucose would be the preferred substrate, which is much less efficient.6

Health & Longevity

  • Anti-carcinogenic properties: Data seems to suggest that exogenous ketones are an effective anti-carcinogen. The reason behind this is that cancer cells are unable to use ketone bodies effectively, unlike most healthy tissues in the body. In fact, dietary ketone supplementation has been shown to increase survival rates of mice with systematic cancer by as much as 70%.7
  • Neuroprotection: As humans age, the brain becomes more susceptible to neurodegeneration and subsequent conditions such as Alzheimer’s and Parkinson’s disease. Exogenous ketone supplementation appears to ameliorate the typical decline in cognitive function that comes with aging. The likely mechanism for this neuroprotective property is that ketone bodies reduce the inflammation and hyperexcitability that is normally exhibited as glucose metabolism declines in the brain.8, 9
  • Anti-Inflammatory properties: There is evidence that ketone bodies play a crucial role in reducing inflammation by inhibiting a specific class of proteins called inflammasones.10
  • Gene regulation profile change. There is evidence that gene sets can be up regulated or down regulated. Still early days but an example of this is a change in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS) in rats on a ketogenic diet.

Mechanisms: How Exogenous Ketones Work

Exogenous ketones have a variety of physiological effects shortly after ingestion:

  • For starters, ingesting ketones (especially ketone esters) is an efficient way to elevate BHB in the blood by upwards of 2 mMol for nearly 8 hours (see Ref. 2). Ketone salts don’t appear to elevate BHB in the blood as efficiently (or significantly) as ketone esters do, though.
  • Exogenous ketone supplementation causes blood glucose to decrease significantly, likely due to the acute increase in insulin sensitivity. Therefore, exogenous ketones may present a potential therapy for type-2 diabetics via regulation of blood glucose.
  • Exogenous ketones also improve oxygen utilization, especially in the central nervous system (CNS).11 This effect decreases the likelihood of oxygen reaching potentially toxic levels in the CNS, which in turn has a number of other positive health ramifications (such as those discussed in the previous section).

Possible Downsides To Ketone Supplementation

As with almost any nutritional supplement, side effects and downsides are possible after consuming exogenous ketones. That being said, they tend to be rather benign and will most likely improve as exogenous ketone supplementation becomes more prominent. The most common side effects to be aware of when using exogenous ketones include:

  • Electrolyte Imbalance – The physiological reasoning behind electrolytes becoming depleted during a state of ketosis is due to lack of water retention and frequent urination. When supplementing with exogenous ketones, the acute state of ketosis will likely increase the frequency of urination, but it won’t deplete glycogen stores. Therefore, it may be useful to drink an electrolyte solution if you are urinating a lot after taking exogenous ketones, but it’s dependent upon how you feel.
  • Halitosis (bad breath) If you’re on a ketogenic diet you are probably aware that as the body starts to metabolize fat, ketones can cause poor breath. There is very little one can do about this, it’s just the nature of the beast. Unfortunately, this can also arise when using exogenous ketones, but it’s not as lasting as when on a ketogenic diet. Chewing gum or mints is about the best option if it becomes a noticeable issue. This maybe caused by over consumption of the ketone supplement, tailoring the quantity consumed may prevent excess BHB being converted to acetone, which is likely excreted by the lungs.
  • Possible GI distress (flatulence) at exceptionally high doses –  In the studies referenced in this article, exogenous ketones taken in large doses occasionally resulted in GI distress, especially flatulence. However, the cause of this is hypothesized to be due to the fact that ketones were mixed in a milky fluid that wasn’t very palatable. If you’re taking a nominal dose of exogenous ketones the likelihood of GI distress is rather low. Moreover, if some GI distress is prevalent, it should improve as you become accustomed to taking ketones.
  • Hypoglycemia: why not to be concerned – Taking exogenous ketones can drive blood glucose levels quite low, but you are not likely to feel the typical symptoms of hypoglycemia. This is because when ketone levels are high enough, they dominate as fuel in the brain; hence, you will feel just fine despite having low blood glucose. A highly-cited study by George Cahill, found elevated ketone levels could protect fasted participants when they were administered insulin to induce hypoglycemia.

Future Applications & Research

Current research on exogenous ketones is heavily focused towards the health and longevity applications of their use. Much of Dominic D’Agostino’s work is currently focused on the cancer prevention aspect of exogenous ketones.

Another area that is targeted, is the psychological benefits of exogenous ketones, especially with how they can help protect brain tissue from degradation. As mentioned earlier, this has implications for the prevention of conditions like Alzheimer’s disease, Parkinson’s disease, and epileptic seizures.

Hopefully, in the not-too-distant future research will also focus more on the athletic performance benefits of exogenous ketones, specifically with regards to resistance training and cardiovascular exercise. The data on each of these applications is very limited at this time.

Further Reading & Recommended Resources

There are a limited group of individuals we recommend you follow to keep up with current findings on exogenous ketones. See the links below:

  • Dominic D’Agostino, Ph.D. – Dr. D’Agostino has his Ph.D. in neuroscience, molecular pharmacology, and physiology; he currently does research focusing on cancer prevention with exogenous ketones. Dominic’s research has largely led the way in the area of exogenous ketones. We interviewed Dominic here.
  • Peter Attia, M.D. – Dr. Attia is a surgeon who studied at Stanford Medical School and did his residency at Johns Hopkins University. He has a passion for helping others lose weight, increase their longevity, and improve their performance (physically and mentally). He has experimented heavily with ketosis, exogenous ketones and ketogenic diets.
  • Richard Veech – Dr. Veech is the senior investigator at the Laboratory of Metabolic Control in Rockville, MD, USA. His research focuses heavily on the role of ketone bodies in regards to preventing metabolic diseases, such as type-2 diabetes.
  • Patrick Arnold – Patrick is an organic chemist who is notorious for being the creator of several performance-enhancing steroids. He is arguably one of the strongest influencers on the advancement of sports supplementation. Currently he is focused on developing products under the KetoSports brand, which includes two exogenous ketone products – KetoForce and KetoCaNa.

Quality Interviews And Blog Posts
  • Super Human Radio Interview: Interview discussing “Best Practices For Using Ketone Salts For Dieting, Performance And Therapeutic Purposes” featuring Dr. Dominic D’Agostino and Patrick Arnold
  • The Eating Academy: Blog post from Dr. Peter Attia on “My Experience with Exogenous Ketones”
  • Quantified Body Podcast: 2 hour long interview discussing the safety, effectiveness and status of ketone mineral salts featuring Dr. Dominic D’Agostino.
  • Tim Ferriss Show Interview with Dominic D’Agostino Discussion includes exogenous ketones for mitigating the onset of neurodegenerative diseases, using ketones in place of fasting for chemo-protection, benefits of ketone supplementation when consuming carbohydrates, the risks and potential toxicities of ketones.
  • KetoVangelist: Dr. Dominic D’Agostino discusses his work with exogenous ketones

Takeaways

Exogenous ketones are likely to be a popular topic of research in the coming years to validate their various uses (physical performance, weight loss, neuro-protective effects). While there is good research about many of these, more data is needed to provide conclusive evidence.

Exogenous ketones certainly appear to have strong health and longevity properties at this point, especially for reducing the risk of cancer and possibly preventing/reversing type-2 diabetes. We recommend reading more from the resources listed above as they are the foremost authorities on current research and findings with regards to exogenous ketones.

Next read Part II in our exogenous ketone series, on exogenous ketone supplements to understand the current ketone supplements available.

References:
  1. I.F. Gaunt, M. Sharratt, J. Colley*, A.B.G. Lansdown, P. Grasso (1970). Acute and short-term toxicity of p-hydroxybenzyl acetone in rats.Food and Cosmetics Toxicology, 8(4), 349-358.
  2. Shannon L. Kesl,corresponding author Angela M. Poff, Nathan P. Ward, Tina N. Fiorelli, Csilla Ari, Ashley J. Van Putten, Jacob W. Sherwood, Patrick Arnold, and Dominic P. D’Agostino (2016). Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague–Dawley rats.Nutrition & Metabolism, 13(9).
  3. Clark, V. L., & Kruse, J. A. (1990). Clinical methods: the history, physical, and laboratory examinations.JAMA, 264(21), 2808-2809.
  4. Cox, P. J., & Clarke, K. (2014). Acute nutritional ketosis: implications for exercise performance and metabolism.Extreme Physiology & Medicine, 3, 17. http://doi.org/10.1186/2046-7648-3-17.
  5. Volek, J. Freidenreich, D.J. Saenz, C. Kunces, L.J. Creighton, B.C. Bartley, J.M. Davitt, P.M. Munoz, C.X. Anderson, J.M. Maresh, C.M. Lee, C.E. Schuenke, M.D. Aemi. G. Kraemer, W.J. Phinney, S.J. (2016). Metabolic characteristics of keto-adapted ultra-endurance athletes.65(3), 100-110.
  6. Yeh, Y. Y., & Sheehan, P. M. (1985, April). Preferential utilization of ketone bodies in the brain and lung of newborn rats. In Federation proceedings (Vol. 44, No. 7, pp. 2352-2358).
  7. Poff, A. M., Ari, C., Arnold, P., Seyfried, T. N., & D’Agostino, D. P. (2014). Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer. International journal of cancer, 135(7), 1711-1720.
  8. Hashim, S. A., & VanItallie, T. B. (2014). Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester.Journal of lipid research, 55(9), 1818-1826.
  9. Hertz, L., Chen, Y., & Waagepetersen, H. S. (2015). Effects of ketone bodies in Alzheimer’s disease in relation to neural hypometabolism, β‐amyloid toxicity, and astrocyte function.Journal of neurochemistry, 134(1), 7-20.
  10. Youm, Y. H., Nguyen, K. Y., Grant, R. W., Goldberg, E. L., Bodogai, M., Kim, D., … & Kang, S. (2015). The ketone metabolite [beta]-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease.Nature medicine, 21(3), 263-269.
  11. D’Agostino, D. P., Pilla, R., Held, H. E., Landon, C. S., Puchowicz, M., Brunengraber, H., … & Dean, J. B. (2013). Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 304(10), R829-R836.

 

Source: ketosource.co.uk

 

 

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